Genetics lesson

For the benefit of our friends and family I'm going to attempt to explain the genetics of Camden's CF and I'll do it with pretty pictures and analogies. I'll probably get some things wrong.

In order to have Cystic Fibrosis you need two defective genes. Apparently both Chelsey and I are carriers of one defective gene. This gene creates proteins in your cells that regulate salt transport (chloride ions actually) across the cell wall. If the cell does not produce the protein correctly (that's the protein over there that looks like party streamers) then the salt balance is messed up in your cells and this leads to problems such as your lung mucus being too thick. Interestingly, that means our cells are messed up too but it turns out you only need a small fraction of the proteins to work. We each have 50% of ours working so we're fine.

Camden inherited two different mutations. One is the classic mutation known as deltaF508. This is shorthand for "There is a deletion of F at position 508." F is shorthand for the amino acid phenylalanine. Because the instructions are missing phenylalanine at that position, the protein folds incorrectly and is destroyed by the cell. It never even makes it to the cell wall. This is known as a Class II mutation i.e. "Defective Protein Processing."

Camden's other mutation is the R117H. This means at position 117, the amino acid arginine (R) is mistakenly replaced by histidine (H). This is interesting because it is not as bad of a mistake. It is known as a Class IV mutation i.e. "Defective Conduction." The protein folds and then makes it all the way to the cell wall but since it isn't quite right, it can't set up the correct chloride or salt flow though the cells. In the case of R117H it maybe can open one chloride channel but not very well and it doesn't open it for long enough.

Got all that? Now for my analogy.

Goin' to the Club.
Think about the cell wall as the entrance to an exclusive club. Having the right protein opens doors. In this case, let's consider the protein to be an outfit.

If you have the right outfit, you can open doors to the club. Need some examples?






This guy is NOT getting into the club.








This guy IS getting into the club.

A properly formed protein is like Carey Grant. In short, suave. A suit and haircut like that open doors.







Camden's situation is that half of his genes (the R117H) look just okay. Not Carey Grant but not Sir Dorks-a-lot up there. The problem is they don't show up to the club in an aston martin, they show up in a rusted out honda. That's fine. At least they got there but they're dressed a little casual for Club Cellular. They'll be asked to wait in line and the doors probably won't open for them.

Consider poor clubbers deltaF508 though. They don't even have a crappy car that works. They can't even get to the club.


Enter Vertex pharmaceuticals. They announced at the end of last month that early results from testing of their new compound, VX-770 are very promising. This drug helps restore the malfunctioning chloride transport at CF patent's cell walls. The drug was tested on people who have a different mutation than Camden.

The drug was tested on people who have at least one G551D mutation. Camden doesn't have this but it is similar to R117H in our analogy in that the club-goers make it to the club. Maybe they drive a 1980 Toyota corolla instead of the Honda but they point is they make it there. Not dressed quite right, they aren't let in and they stand in line like our friends R117H. What VX-770 does is it tells the bouncer to go ahead and let everyone standing in line into the club. Woo hoo! Party Time!

So, where does that leave Camden? The R117H mutation is one of the milder ones. It is similar to G551D in that the proteins created do "localize to the cell wall" Given that the proteins created by the faulty R117H mutation do reach the cell wall, this is the second mutation Vertex is testing VX-770 on. You can see here in the clinical trail description, they are looking for people with his mutation to take part in part two of the Phase 2a trial.

We're hoping to see similar results with part two of the study which would mean it works for people with the R117H mutation.

Interestingly, Vertex has a second drug in very early testing called VX-809 that is designed to get faulty proteins to the cell wall. Think of it as taking a limo to the club when your car is broken down. While we're really excited about the possibility of VX-770 for Cam (pending results of this next trial) the real hope for most people with CF is that these two drugs together could work to actually treat the cause of CF rather than the symptoms. The Limo (VX-809) gets you to the club and then an Andrew Jackson (VX-770) slipped to the bouncer gets you into the club.

The clinical trial only really looked at lung function and sweat conductance and not digestion which is the other big part of CF. I found this in an article though, "In young patients the pancreas and digestive tract also may benefit from the drug, says Vertex Chief Medical Officer John Alam, because the CFTR function is suspected to play a role there as well." So, that sounds promising.

At any rate, it will be years before any drug is on the market. Camden's doctor told us he is really excited about the drug and will be writing Cam a prescription the first day it is available.

At his appointment today he weighed in at 14 lbs, 9 oz. That's a gain of over two pounds in one month! They were hoping he would gain at least a pound a month so this is great news. He is still technically "nutritionally insufficient" however because he also grew over one inch in that same month. That means the height/weight ratio is skewed and he needs to weigh even more given that he is getting so tall. The fuss over weight is because lung function is correlated with weight in CF patients so by keeping his weight up it will hopefully keep his lungs healthier.